In 1981, acquired immune deficiency syndrome (AIDS) was identified as a disease that severely compromises the human immune system that almost without exception leads to death. In 1983, the etiological cause of AIDS was determined to be the HIV.
In 1985, it was reported that the synthetic nucleoside 3′-azido-3′-deoxythymidine (AZT) inhibits the replication of HIV. Since then, a number of other synthetic nucleosides, including 2′,3′-dideoxyinosine (DDI), 2′,3′-dideoxycytidine (DDC), and 2′,3′-dideoxy-2′,3′-didehydrothymidine (D4T), have been proven to be effective against HIV. After cellular phosphorylation to the 5′-triphosphate by cellular kinases, these synthetic nucleosides are incorporated into a growing strand of viral DNA, causing chain termination due to the absence of the 3′-hydroxyl group. They can also inhibit the viral enzyme reverse transcriptase.
The success of various synthetic nucleosides in inhibiting the replication of HIV in vivo or in vitro has led a number of researchers to design and test nucleosides that substitute a heteroatom for the carbon atom at the 3′-position of the nucleoside (Norbeck et al. 1989, Tetrahedron Letters, 30 (46) 6246, European Patent Application Publication No. 0 337 713, and U.S. Pat. No. 5,041,449).
U.S. Pat. No. 5,047,407 and European Patent Application Publication No. 0 382 526, disclose a number of racemic 2′-substituted-5′-substituted-1,3-oxathiolane nucleosides with antiviral activity, and specifically report that the racemic mixture (about the C4′-position) of the C1′-β isomer of 2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (±)-BCH-189) has approximately the same activity against HIV as AZT, and no cellular toxicity at the tested levels. (±)-BCH-189 has also been found to inhibit the replication of AZT-resistant HIV isolates in vitro from patients who have been treated with AZT for longer than 36 weeks. The (−)-enantiomer of the isomer of BCH-189, known as 3TC, is highly potent against HIV and exhibits little toxicity. (−)-cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (“FTC”) also has potent HIV activity (Schinazi et al. 1992 Antimicrob. Agent and Chemotherap, 2423-2431).
Recently, 4′-C-substituted nucleosides have been reported to show potent anti-HIV activity (Siddiqui, M. A. et al. J. Med. Chem. 2004, 47, 5041-5048; Nomura, M. et al. J. Med. Chem. 1999, 42, 2901-2908).
Another virus that causes a serious human health problem is HBV. HBV is second only to tobacco as a cause of human cancer. The mechanism by which HBV induces cancer is unknown, although it is postulated that it may directly trigger tumor development, or indirectly trigger tumor development through chronic inflammation, cirrhosis, and cell regeneration associated with the infection.
After a two to six month incubation period in which the host is unaware of the infection, HBV infection can lead to acute hepatitis and liver damage that causes abdominal pain, jaundice, and elevated blood levels of certain enzymes. HBV can cause fulminant hepatitis, a rapidly progressive, often fatal form of the disease in which massive sections of the liver are destroyed.
In western industrialized countries, high-risk groups for HBV infection include those in contact with HBV carriers or their blood samples. The epidemiology of HBV is very similar to that of acquired immune deficiency syndrome, which accounts for why HBV infection is common among patients with AIDS or AIDS-related complex. However, HBV is more contagious than HIV. Both FTC and 3TC exhibit activity against HBV (Furman et al. 1992 Antimicrobial Agents and Chemotherapy, 2686-2692).
A human serum-derived vaccine has been developed to immunize patients against HBV. While it has been found effective, production of the vaccine is troublesome because the supply of human serum from chronic carriers is limited, and the purification procedure is long and expensive. Further, each batch of vaccine prepared from different serum must be tested in chimpanzees to ensure safety. Vaccines have also been produced through genetic engineering. Daily treatments with α-interferon, a genetically engineered protein, have also shown promise.
In light of the fact that acquired immune deficiency syndrome, AIDS-related complex, and hepatitis B virus have reached epidemic levels worldwide, and have tragic effects on the infected patient, there remains a strong need to provide new effective pharmaceutical agents to treat these diseases and that have low toxicity to the host.